The effect of age on the discriminative stimulus effects of ethanol and its GABAA receptor mediation in cynomolgus monkeys

Abstract

Rationale Excessive alcohol consumption is less common among aged compared to young adults, with aged adults showing greater sensitivity to many behavioral effects of ethanol. Objectives This study compared the discriminative stimulus effects of ethanol in young and middle-aged adult cynomolgus monkeys (Macaca fascicularis) and its γ-amino-butyric acid (GABA)A receptor mediation. Methods Two male and two female monkeys trained to discriminate ethanol (1.0 g/kg, i.g.; 60-min pre-treatment interval) from water at 5-6 years of age (Grant et al. 2000) were re-trained in the current study more than a decade later (19.3 ± 1.0 years of age) for a within-subjects comparison. Also, four experimentally-naïve middle-aged (mean ± SEM, 17.0 ± 1.5 years of age) female monkeys were trained to discriminate ethanol for between-subjects comparison with published data from young adult naïve monkeys. Results Two of the naïve middle-aged monkeys attained criterion performance, with weak stimulus control and few discrimination tests, despite greater blood-ethanol concentration (BEC) 60 min after 1.0 g/kg ethanol in middle-aged compared to young adult female monkeys (Green et al. 1999). The efficacy of the GABAA receptor positive modulators pentobarbital, midazolam, allopregnanolone, pregnanolone and androsterone to substitute for the discriminative stimulus effects of 1.0 g/kg ethanol was maintained from young adulthood to middle age. Conclusions The data suggest that 1.0 g/kg ethanol is a weak discriminative stimulus in naive middle-aged monkeys. Nevertheless, the GABAA receptor mechanisms mediating the discriminative stimulus effects of ethanol, when learned as a young adult, appear stable across one-third of the primate lifespan.

The discriminative stimulus effects of a nicotine-ethanol compound in rats: Extinction with the parts differs from the whole.

“…Ethanol, for example, has been shown to be complex multielement discriminative stimulus with serotonergic, glutmatergic, dopamingergic, opioid, and GABAergic components (Grant, 1999;Kostowski & Bietikowsi, 1999;Stolerman, Mariathasan, White, & Olufsen, 1999). A future investigation might substitute other GABA agonists (Helms & Grant, 2011), glutamate antagonists (Besheer et al, 2009), serotonin agonists (Grant, Colombo, & Gatto, 1997), or mu opiate agonists (Plat & Bano, 2011) during extinction to determine the relative impact on responding evoked by the original ethanol S^. Additionally, other cholingergic ligands such as varenicline could be substituted during opérant extinction (cf Reichel, Murray, Barr, & Bevins, 2010, for a Pavlovian analog).…”

Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol

“…Nonhuman primate studies have primarily focused on ethanol’s action at the GABA A and NMDA receptors, with some work on the opioid system. Additionally, nonhuman primate work has examined other biological variables that may contribute to ethanol’s discriminative stimulus effects, such as sex [73–76], age [77], and menstrual cycle [78]. …”

“…In the luteal phase, when progesterone levels are high, allopregnanolone is more potent in its substitution for ethanol, consistent with greater levels of allopregnanolone in the plasma. Lastly, one study examined the effect of age on ethanol discriminative stimulus effects and determined that ethanol served as a relatively weaker stimulus in middle-aged monkeys, despite elevated blood ethanol concentrations relative to when the same monkeys were young adults [77]. Additionally, this study demonstrated that ethanol discrimination was persistent and demonstrated up to 3 years without any intermediate training [77].…”

Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats

“…In a recent study in our laboratory of the effects of aging in cynomolgus macaques that previously acquired ethanol discrimination, a female monkey that had been trained to discriminate 1.0 g/kg ethanol over a decade earlier demonstrated a decrease in the substitution potency of ethanol with age, which further decreased after bilateral ovariectomy (Helms and Grant, 2011). This trend suggests that the absence of ovarian-derived hormones alters the mechanisms mediating the discrimination of ethanol.…”